Method for preventing, reducing, and treating radiation cystitis using hyaluronic acid

ABSTRACT

A method for preventing, reducing or treating radiation cystitis caused by external beam radiation therapy, which impinges on the urinary bladder and associated structures, comprising administering into the urinary bladder and associated structures a composition comprising hyaluronic acid (HA) having an average molecular weight of not less than 2×10 5  Daltons and a pharmaceutically acceptable carrier.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional ApplicationSerial No. 60/105,184, filed Oct. 22, 1998.

TECHNICAL FIELD

[0002] The present invention relates to a method for preventing,reducing and treating radiation cystitis caused by external beamradiation therapy, which impinges on the urinary bladder and associatedstructures, comprising administering into the urinary bladder andassociated structures a composition comprising hyaluronic acid (HA)having an average molecular weight of not less than 2×10⁵ Daltons and apharmaceutically acceptable carrier.

BACKGROUND OF THE INVENTION

[0003] Carcinoma of the prostate is among the most common forms ofcancer and of cancer mortality in males. External beam radiation therapy(hereinafter, radiotherapy) is widely used for patients with clinicallylocalized carcinoma of the prostate and is standard therapy for patientsdiagnosed with extensive local disease (American Joint Committee onCancer). Radiotherapy also is used for patients with clinicallylocalized carcinoma of the bladder, rectum, uterus and cervix.

[0004] Acute effects of radiotherapy on normal tissue are observedduring and immediately following a course of radiotherapy. The majorcomplication of radiotherapy, which impinges on the bladder area, is itseffect on urinary bladder function resulting in radiation cystitis.Radiation cystitis is defined in terms of bladder pain, increasedurinary urgency, increased voiding frequency and increased nocturia. Itsduration is usually 3 to 6 months, but can be 24 months or longer.Moreover, serious delayed urinary complications involving lifestylealtering symptoms or requiring hospitalization are observed in 2-7% ofpatients undergoing radiotherapy for prostate cancer.

[0005] It is hypothesized that radiation of the bladder area inducesdisruption of the glycosaminoglycan (GAG) layer, which lines the innersurface of the urinary bladder. This GAG layer consists ofmucopolysaccharides attached to a core protein that, in turn, is boundto a central hyaluronic acid string. This highly viscous, highlyhydrophilic GAG layer protects the bladder epithelium against irritantsin the urine including, but not limited to, microorganisms, pathogens,microcrystals, proteins, calcium, urea and carcinogens (Nickel et al.1993. Journal of Urology, 149:716). When this protective barrier isdamaged, the bladder epithelium becomes permeable to urinary irritants,resulting in symptoms of bladder pain, increased urinary urgency,increased voiding frequency and increased nocturia. Other symptoms caninclude, but are not limited to, dysuria, heamaturia, arthritis, spasticcolon, low grade fever and irritability.

[0006] Methods for treating existing interstitial cystitis include, butare not limited to, hydraulic distention of the urinary bladder, oralamitriptyline or sodium pentosanpolysulfate, intravesical instillationof dimethyl-sulfoxide, oxychlorosene sodium, silver nitrate, heparin,angiostatic steroids, pentosanpolysulfate and hyaluronic acid.

[0007] However, what is needed is a method for protecting the urinarybladder from the effects of the radiotherapy so as to prevent, reduceand treat the radiation cystitis caused by radiotherapy that impinges onthe bladder area.

SUMMARY OF THE INVENTION

[0008] A method is provided for preventing, reducing and treatingradiation cystitis caused by radiotherapy that impinges on the urinarybladder of an animal, including a human, comprising administering intothe bladder of the animal a composition comprising HA, having an averagemolecular weight of not less than 2×10⁵ Daltons, and a pharmaceuticallyacceptable carrier, wherein the HA is administered in an amounteffective to prevent, reduce and treat the radiation cystitis.

[0009] It is an object of the present invention to provide a method forpreventing radiation cystitis.

[0010] It is another object of the present invention to provide a methodfor preventing radiation cystitis that has minimal side effects.

[0011] It is another object of the present invention to provide a methodfor preventing radiation cystitis that is minimally invasive.

[0012] It is another object of the present invention to provide a methodfor preventing radiation cystitis in an individual undergoingradiotherapy for bladder cancer.

[0013] It is another object of the present invention to provide a methodfor preventing radiation cystitis in an individual undergoingradiotherapy for prostate cancer.

[0014] It is another object of the present invention to provide a methodfor preventing radiation cystitis in an individual undergoingradiotherapy for rectal cancer.

[0015] It is another object of the present invention to provide a methodfor preventing radiation cystitis in an individual undergoingradiotherapy for uterine cancer.

[0016] It is another object of the present invention to provide a methodfor preventing radiation cystitis in an individual undergoingradiotherapy for cervical cancer.

[0017] It is another object of the present invention to provide a methodfor reducing radiation cystitis

[0018] It is another object of the present invention to provide a methodfor reducing radiation cystitis that has minimal side effects.

[0019] It is another object of the present invention to provide a methodfor reducing radiation cystitis that is minimally invasive.

[0020] It is another object of the present invention to provide a methodfor reducing radiation cystitis in an individual undergoing radiotherapyfor bladder cancer.

[0021] It is another object of the present invention to provide a methodfor reducing radiation cystitis in an individual undergoing radiotherapyfor prostate cancer.

[0022] It is another object of the present invention to provide a methodfor reducing radiation cystitis in an individual undergoing radiotherapyfor rectal cancer.

[0023] It is another object of the present invention to provide a methodfor reducing radiation cystitis in an individual undergoing radiotherapyfor uterine cancer.

[0024] It is another object of the present invention to provide a methodfor reducing radiation cystitis in an individual undergoing radiotherapyfor cervical cancer.

[0025] It is another object of the present invention to provide a methodfor treating radiation cystitis after completion of a course ofradiotherapy.

[0026] It is another object of the present invention to provide a methodfor treating radiation cystitis after completion of a course ofradiotherapy that has minimal side effects.

[0027] It is another object of the present invention to provide a methodfor treating radiation cystitis after completion of a course ofradiotherapy that is minimally invasive.

[0028] It is another object of the present invention to provide a methodfor treating radiation cystitis in an individual after completion of acourse of radiotherapy for bladder cancer.

[0029] It is another object of the present invention to provide a methodfor treating radiation cystitis in an individual after completion of acourse of radiotherapy for prostate cancer.

[0030] It is another object of the present invention to provide a methodfor treating radiation cystitis in individuals after completion of acourse of radiotherapy for rectal cancer.

[0031] It is another object of the present invention to provide a methodfor treating radiation cystitis in an individual after completion of acourse of radiotherapy for uterine cancer.

[0032] It is another object of the present invention to provide a methodfor treating radiation cystitis in an individual after completion of acourse of radiotherapy for cervical cancer.

[0033] Other objects, features and advantages of the present inventionwill become apparent upon reading the following detailed description ofthe invention when taken in conjunction with the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

[0034] As used herein, the word “bladder” refers to the internal surfaceof the urinary bladder and its associated structures in an animal,including a human.

[0035] As used herein, the phrase “associated structures” refers to therenal pelvis, ureters and urethra in an animal, including a human.

[0036] As used herein, the phrase “internal surface of the urinarybladder” refers to the transitional epithelium, which lines the urinarybladder and associated structures in an animal, including a human.

[0037] As used herein, the phrase “radiation cystitis” refers tosymptoms selected from the group consisting of bladder pain, increasedurinary urgency, increased voiding frequency and increased nocturia thatare associated with radiotherapy that impinges on the bladder.

[0038] HA is highly viscous, highly electronegative and highlyhydrophilic. It has been found that contacting the bladder with asolution containing an effective concentration of HA and salts thereof,having an average molecular weight of not less than 2×10⁵ Daltons, priorto radiotherapy, during a course of radiotherapy treatments,unexpectedly prevents or reduces the symptoms of radiation cystitisusually caused by radiotherapy for diseases such as, but not limited to,prostate cancer, bladder cancer, rectal cancer, uterine cancer andcervical cancer. It also has been found that contacting the bladder witha solution containing an effective concentration of HA and saltsthereof, having an average molecular weight of not less than 2×10⁵Daltons, subsequent to completion of a course of radiotherapy treatmentsunexpectedly treats the symptoms of radiation cystitis caused byradiotherapy for diseases such as, but not limited to, prostate cancer,bladder cancer, rectal cancer, uterine cancer and cervical cancer.Preferably the HA has a molecular weight range of about 2×10⁵ to about3.1×10⁶ Daltons, more preferably of about 2×10⁵ to about 1.9×10⁶ Daltonsand most preferably of about 2.5×10⁵ to about 1.2×10⁶ Daltons.

[0039] Various methods for the isolation, purification and fractionationof hyaluronic acid are available. These include fractionation of HAderived from cartilage, fractionation of hyaluronic acid derived frombacteria including, but not limited to, streptococcal species, and thepurchase of molecular weight fractions of hyaluronic acid fromcommercial sources including, but not limited to, Fluka ChemicalCorporation, Ronkonkoma, N.Y., Genzyme Corporation, Cambridge, Mass. andLifecore Biomedical, Inc., Chaska, Minn.

[0040] For use in the present invention, the HA is solubilized in apharmaceutically acceptable carrier including, but not limited to,physiological saline and phosphate buffered saline. However, it is to beunderstood that any of the pharmaceutical carriers known to thoseskilled in the art to be acceptable for administration into the bladderof an animal can be used in the present invention.

[0041] HA is administered into the bladder in an amount between about 5mg and about 1000 mg, more preferably between about 10 mg and about 500mg and most preferably between about 25 mg and about 100 mg. Theconcentration of HA administered into the bladder is preferably fromabout 0.01 mg/ml to about 100 mg/ml, more preferably from about 0.1mg/ml to about 50 mg/ml and most preferably from about 0.4 mg/ml toabout 25 mg/ml. The volume of HA solution administered into the bladderis between about 1 ml and about 500 ml, more preferably between about 10ml and about 250 ml and most preferably between about 20 ml and about100 ml.

[0042] To prevent or to reduce radiation cystitis, HA solution can beadministered into the bladder prior to a radiotherapy treatment and/orsubsequent to a radiotherapy treatment. It can be used in conjunctionwith each radiotherapy treatment or in conjunction with any multiple ofradiotherapy treatments. To treat radiation cystitis, HA solution can beadministered into the bladder one or more times after completion of acourse of radiotherapy treatments.

[0043] Prior to installation of HA solution, residual urine is removedfrom the bladder using a sterile urethral catheter. The HA solution isthen administered into the bladder using, but not limited to, a sterileurethral catheter. However, it is to be understood that any method knownto those skilled in the art for administering a pharmaceuticalcomposition into the bladder of an animal can be used in the presentinvention.

[0044] HA solution is administered into the bladder from about 1 minuteto about 4 hours prior to a radiotherapy treatment or subsequent to aradiotherapy treatment, more preferably from about 2 minutes to about 2hours and most preferably from about 5 minutes to about 1 hour. HAsolution also is administered into the bladder after completion of acourse of radiotherapy treatments. Whether administered prior to aradiotherapy treatment, subsequent to a radiotherapy treatment or aftercompletion of a course of radiotherapy treatments, the HA solutionremains in contact with the bladder for a total time of about 1 minuteto about 4 hours, more preferably from about 2 minutes to about 2 hoursand most preferably from about 5 minutes to about 1 hour.

[0045] The HA solution may further include agents such as, but notlimited to, antiseptic, antibacterial, antifungal, immunotherapeutic,immunosuppressive, chemotherapeutic, pH modifying, and glycosaminoglycan(in addition to HA) agents. The agent and the amount of the agent to beincluded in the HA solution are well within the determination of thoseskilled in the art.

[0046] Antibacterial agents include, but are not limited to,aminoglycoside, cephalosporin, gentamycin, macrolide, nitrofurantoin,penicillin, quinolone, sulphonamide, tetracycline, trimethoprim,bacitracin, neomycin, chlorhexidine and mandelamine. Antifungal(antiyeast) agents include, but are not limited to, amphotericin B andfluconazole. Immunotherapeutic agents include, but are not limited to,bacterial cell extracts, mycobacterial cell wall extracts, live andinactivated bacillus Calmette-Guerin (BCG), BCG extracts, cytokines,interferons, interleukins, prostaglandins, and immune stimulants ofviral, chemical and molecular biological origin effective for treatingdisorders of the bladder and the associated cystitis. Immunosuppressiveagents include, but not limited to, prostaglandins (PGE₂) andcorticosteroids. Chemotherapeutic agents include, but are not limitedto, cisplatin, cyclophosphamide, doxorubicin (adriamycin), vincristine,mitomicin-C and thiotepa. pH modifying agents include, but are notlimited to, sodium acid phosphate and sodium bicarbonate.Glycosaminoglycans (in addition to HA) include, but are not limited to,heparin, heparan sulfates, pentosanpolysulfate, dermatan sulfates,chondroitin sulfates and keratanosulfates.

EXAMPLE 1

[0047] Patient Selection

[0048] Inclusion criteria include patients >18 years of age withhistologically documented stage T2 or T3 (T3a or T3b) prostate carcinomaand PSA within normal range following anti-androgen therapy (<60 years,upper limit of 4.0 ng/ml; 60-69 years, upper limit 4.5 ng/ml; >70 years,upper limit of 6.5 ng/ml). These patients have an ECOG performancestatus for cancer clinical trials of 0, 1 or 2 (Oken et al. AmericanJournal of Clinical Oncology (CCT), 5:649, 1982), a five-year lifeexpectancy and are available for at least one year. They have normalwhite blood cell count, platelets, international normalized ratio ofprothrombin time and partial thromboplastin time.

[0049] Exclusion criteria include patients being treated withinvestigational drugs, anticholinergics, urinary antiseptics,antihistamines, potent analgesics, corticosteroids, anti-inflammatoryagents or any medication or active treatment for interstitial cystitiswithin 14 days of radiotherapy, patients with clinical evidence ofmetastatic disease, multiple transurethral resections of bladder tumorsor recurring bladder infections or stones, collagen, vascular, orautoimmune disease, ulcerative colitis or regional enteritis, multipleprior abdominal surgical procedures, renal insufficiency (Blood UreaNitrogen >15 mmol/L, serum creatinine >250 μmmol/L), hepaticinsufficiency (Alanine Aminotransferase and AspartateAminotransferase>50% above upper limit of normal), uncontrolledcongestive heart failure or uncontrolled ischemic heart disease andprevious chemotherapy and/or radiation therapy.

EXAMPLE 2

[0050] Pre-therapy (baseline) Assessment

[0051] Pre-therapy pain scale, urinary urgency (urgency) scale, voidingfrequency and nocturia are obtained 3 times during week 0 (pre-therapy)using patient recorded (diary) assessments. Pre-therapy symptom indexand problem index is assessed 1 time during week 0 using patientadministered questionnaires. The scales and indices used are known tothose skilled in the art.

[0052] Pain scales include the Visual Analog Scale (VAS 0-10 cm), the 6Point Behavioral Rating Scale (BRS6) and 5 Point Verbal Rating Scale(VRS5). Urgency is defined as a strong need to urinate with little or nowarning. Urgency scales include the Visual Analog Scale (VAS 0-10 cm)and the Point Verbal Rating Scale (VRS-5). Voiding frequency measuresthe frequency of urination during a 24 hour time period and nocturiameasures the frequency of waking up to urinate during sleep. The symptomindex measures radiation cystitis symptoms, which occur during aspecified time period (O'Leary et al., Journal of Urology 155(515):439A,1996). The problem index measures lifestyle problems related toradiation cystitis.

EXAMPLE 3

[0053] Radiation Protocol

[0054] A radiotherapy dose of 18-220 cGY per day is given 5 days perweek for 6 weeks and 3 times per week for 1 additional week (33treatments) resulting in a total dose of 6600 cGY.

EXAMPLE 4

[0055] HA Protocol

[0056] HA solution is administered into the bladder about 30 minutesprior to radiotherapy 3 times per week (alternate days) for 6 weeks and2 times per week for 1 additional week (20 treatments).

[0057] To do this, a urethral catheter is introduced into the bladderunder aseptic conditions, residual urine is removed and the volumerecorded. Fifty ml of sterile PBS containing about 40 mg of HA, havingan average molecular weight of about 6.5×10⁵ Daltons (range 5×10⁵ to7.3×10⁵ Daltons), is administered into the bladder through the catheter.The HA solution is maintained in the bladder for about 30 minutes, theHA solution is voided and the radiotherapy is begun.

EXAMPLE 5

[0058] During Therapy Assessment

[0059] During the 7 weeks of radiotherapy, pain scale, urgency scale,voiding frequency and nocturia are obtained 3 times per week usingpatient recorded (diary) assessments as in Example 2. Symptom index andproblem index is assessed at weeks 4 and 8 using patient administeredquestionnaires as in Example 2.

EXAMPLE 6

[0060] Outcome Criteria

[0061] As pain scale, urgency scale, symptom index and problem index aresubjective assessments, each patient undergoing radiotherapy forprostate cancer was used as his own control. To do this, the average ofpain scales, urgency scales, voiding frequencies and nocturia reportedduring weeks 6 and 7 of radiotherapy and symptom index and problem indexreported at week 8 (post-therapy) were compared to the average of painscales, urgency scales, voiding frequencies and nocturia and symptomindex and problem index reported during week 0 (pre-therapy).

[0062] Outcome Criteria Include:

[0063] A. HA Administered During Course of Radiotherapy:

[0064] 1. Prevention of symptoms of radiation cystitis—decreases or noincreases in average pain scale, average urgency scale, average voidingfrequency or average nocturia during weeks 6 and 7 of radiotherapycompared to week 0 and decreases or no increases in symptom index and inproblem index at week 8 compared to week 0.

[0065]2. Reduction in symptoms of radiation cystitis—minimal increasesin average pain scale of ≦1.0, average urgency scale of ≦1.0, averagevoiding frequency of ≦5, and average nocturia of ≦3 during weeks 6 and 7of radiotherapy compared to week 0 and minimal increases in symptomindex of ≦3 and problem index of ≦3 at week 8 compared to week 0.

[0066]3. Ineffective to prevent or reduce symptoms of radiationcystitis—significant increases in average pain scale of >1.0, averageurgency scale of >1.0, average voiding frequency of >5, and averagenocturia of >3 during weeks 6 and 7 of radiotherapy compared to week 0and significant increases in symptom index of >3 and problem index of >3at week 8 compared to week 0.

[0067]4. Patient withdraws or is withdrawn from the study.

[0068] B. HA Administered at Completion of a Course of Radiotherapy:

[0069] 1. Treatment of symptoms of radiation cystitis—significantdecreases in average pain scale of ≧1.0, average urgency scale of ≧1.0,average voiding frequency of ≧5, and average nocturia of ≧3 during weeks12 and 13 after radiotherapy compared to weeks 6 and 7 of radiotherapyand decreases in symptom index of ≧3 and problem index of 23 at week 14after radiotherapy compared to weeks 6 and 7 of radiotherapy.

[0070] 2. Ineffective to treat symptoms of radiation cystitis- minimaldecreases in average pain scale of <1.0, average urgency scale of <1.0,average voiding frequency of <5, and average nocturia of <3 during weeks12 and 13 after radiotherapy compared to weeks 6 and 7 of radiotherapyand decreases in symptom index of. <3 and problem index of <3 at week 14after radiotherapy compared to weeks 6 and 7 of radiotherapy.

[0071] 3. Patient withdraws or is withdrawn from the study.

EXAMPLE 7

[0072] Radiotherapy Without HA

[0073] Patients, selected as in Example 1, receive radiotherapy as inExample 3. These patients have increases in average pain scale >1.0,average urgency scale of >1.0, average voiding frequency of >5 andaverage nocturia of >3 during weeks 6 and 7 of radiotherapy compared toweek 0 and increases in symptom index of >3 and in problem index of >3at week 8 compared to week 0.

[0074] By weeks 6 and 7, each of these patients reports passage of smallamounts of urine with burning pain, voiding frequencies of >20 times perday and nocturia of >8 times per night.

[0075] Therefore, patients who do not receive administration of HA intothe bladder, prior to radiotherapy treatments during a course ofradiotherapy that impinges on the bladder, develop the bladder pain,increased urgency, increased voiding frequency and increased nocturiasymptomatic of radiation cystitis.

EXAMPLE 8

[0076] Radiotherapy with Concurrent HA

[0077] Five patients, selected as in Example 1, elected to receive HA asin Example 4 prior to radiotherapy treatments during the course of theirradiotherapy for prostate cancer as in Example 3.

[0078] Table 1 shows results obtained for Patient A during weeks 1-7 ofradiotherapy and at the completion of radiotherapy (week 8). TABLE 1Patient A Ur- Symp- Pain gency Frequency Nocturia tom Problem Week DayVAS VAS Times/24 h Times Index Index 0 3 ND ND ND ND 3 0 1 1 0   0.1 8 02 ND 0.1 8 0 3 ND ND 8 0 2 1 0.1 ND 5 0 2 ND ND 7 0 3 ND ND 7 0 3 1 0.10.2 8 0 3 ND 1.0 7 1 4 1 ND 0.0 7 1 2 1 2 ND ND 7 1 3 0.1 0.1 7 1 5 1 NDND 8 0 2 0.2 0.2 7 1 3 0.2 0.4 7 3 6 1 ND ND 7 1 2 0.2 0.1 7 1 3 0.2 0.28 2 7 1 0.2 0.2 7 2 2 0.2 ND 7 2 8 1 2 1

[0079] As pre-therapy (week 0) data for pain scale, urgency scale,voiding frequency and nocturia were not available for this patient, week1 averages were used as baseline. For week 1, pain scale was 0.0 andincreased to 0.2 during weeks 6 and 7 of radiotherapy. For week 1,urgency scale was 0.0 and increased to 0.17 during weeks 6 and 7 ofradiotherapy. For week 1, voiding frequency was 8.0 and decreased to 7.3during weeks 6 and 7 of radiotherapy. For week 1, nocturia was 0.0 andincreased to 1.7 during weeks 6 and 7 of radiotherapy. The symptom indexdecreased from 3 to 2 and the problem index increased from 0 to 1between weeks 0 and 8.

[0080] These data show that administration of HA into the bladder ofPatient A prior to radiotherapy treatments during a course ofradiotherapy either prevented or reduced the pain, increased urgency,increased voiding frequency and increased nocturia usually associatedwith radiotherapy for the treatment of prostate cancer.

[0081] Table 2 shows results obtained for Patient B prior toradiotherapy (week 0), during radiotherapy (weeks 1-7) and at thecompletion of radiotherapy (week 8). TABLE 2 Patient B Ur- FrequencyNoc- Pain gency Times/ turia Symptoms Problems Week Day VAS VAS 24 hTimes Index Index 0 1 0.2 0.3 5 3 5 8 2 0.1 0.3 11 3 3 0.1 0.1 9 2 1 10.1 0.2 8 3 2 0.2 0.2 11 3 3 0.1 0.2 10 4 2 1 0.2 0.8 8 5 2 0.2 0.8 11 63 0.1 0.7 12 4 3 1 0.1 0.8 12 3 2 0.1 0.6 15 4 3 0.1 0.6 13 3 4 1 0.10.9 12 4 4 9 2 0.1 0.5 14 4 3 0.1 0.1 11 4 5 1 0.1 0.8 10 4 2 0.0 0.0 114 3 0.1 1.0 13 4 6 1 0.1 0.5 13 2 2 0.1 0.5 12 2 3 0.1 0.5 14 3 7 1 0.11.0 15 4 2 0.1 0.5 13 5 8 1 4 7

[0082] For week 0, pain scale was 0.13 and remained relatively unchangedat 0.10 during weeks 6 and 7 of radiotherapy. For week 0, urgency scalewas 0.23 and increased to 0.60 during weeks 6 and 7 of radiotherapy. Forweek 0, voiding frequency was 8.3 and increased to 13.4 during weeks 6and 7 of radiotherapy. For week 0, nocturia was 2.7 and increased to 3.2during weeks 6 and 7 of radiotherapy. The symptom index decreased from 5to 4 and the problem index decreased from 8 to 7 between weeks 0 and 8.

[0083] These data show that administration of HA into the bladder ofPatient B prior to radiotherapy treatments during a course ofradiotherapy reduced the pain, increased urgency, increased voidingfrequency and increased nocturia usually associated with radiotherapyfor the treatment of prostate cancer.

[0084] Table 3 shows results obtained for Patient C prior toradiotherapy (week 0), during radiotherapy (weeks 1-7) and at thecompletion of radiotherapy (week 8). TABLE 3 Patient C Ur- FrequencyNoc- Pain gency Times/ turia Symptoms Problems Week Day VAS VAS 24 hTimes Index Index 0 1 0.2 6.8 7 2 6 4 2 0.2 5.0 7 1 3 0.2 4.8 7 2 1 10.2 5.0 5 1 2 0.2 5.1 8 2 3 0.2 5.0 9 1 2 1 0.2 4.9 10 1 2 0.1 5.2 11 23 0.2 2.6 6 3 3 1 0.1 5.2 6 2 2 0.2 5.2 8 2 3 0.2 2.5 7 3 4 1 0.1 4.3 84 7 8 2 0.1 4.3 11 3 3 0.1 2.0 8 1 5 1 0.1 4.3 12 2 2 0.0 2.0 9 2 3 0.14.3 10 3 6 1 0.1 2.0 10 4 2 0.1 2.0 12 2 3 0.1 2.0 9 2 7 1 0.1 2.0 11 12 0.1 2.0 10 4 8 1 11 12

[0085] For week 0, pain scale was 0.20 and remained relatively unchangedat 0.10 during weeks 6 and 7 of radiotherapy. For week 0, urgency scalewas 5.5 and decreased to 2.0 during weeks 6 and 7 of radiotherapy. Forweek 0, frequency was 7 and increased to 10.4 during weeks 6 and 7 ofradiotherapy. For week 0, nocturia was 1.7 and increased to 2.6 duringweeks 6 and 7 of radiotherapy. The symptom index increased from 8 to 11and the problem index increased from 5 to 12 between weeks 0 and 8.

[0086] Although Patient C reported no change in pain scale, a decreasein urgency scale and minimal increases in voiding frequency and nocturiabetween week 0 and weeks 6 and 7, he reported significant increases insymptom index and in problem index between weeks 0 and 8. Nevertheless,these data show that administration of HA into the bladder of Patient Cprior to radiotherapy treatments during a course of radiotherapy eitherprevented or reduced the pain, increased urgency, increased voidingfrequency and increased nocturia usually associated with radiotherapyfor the treatment of prostate cancer.

[0087] Table 4 shows results obtained for Patient D prior toradiotherapy (week 0), during radiotherapy (weeks 1-7) and at thecompletion of radiotherapy (week 8). TABLE 4 Patient D Ur- FrequencyNoc- Pain gency Times/ turia Symptoms Problems Week Day VAS VAS 24 hTimes Index Index 0 1 0.0 4.5 9 3 3 1 2 0.0 3.5 9 3 3 0.0 2.2 8 3 1 10.0 3.2 10 5 2 0.0 1.9 8 2 3 0.0 1.8 7 2 2 1 0.0 1.8 10 3 2 0.0 1.9 9 33 0.0 1.6 11 3 3 1 0.0 2.2 11 5 2 0.0 4.5 10 3 3 0.0 3.1 10 4 4 1 0.02.8 11 5 4 1 2 0.0 6.8 9 3 3 0.0 1.7 11 4 5 1 0.0 2.3 11 4 2 0.0 3.9 103 3 0.0 3.0 10 4 6 1 0.0 3.4 12 6 2 0.0 4.2 12 5 3 0.0 3.0 12 4 7 1 0.02.5 13 4 8 1 4 1

[0088] For week 0, pain scale was 0.0 and remained unchanged at 0.0during weeks 6 and 7 of radiotherapy. For week 0, urgency scale was 3.4and remained essentially unchanged at 3.3 during weeks 6 and 7 ofradiotherapy. For week 0, frequency was 8.7 and increased to 12.2 duringweeks 6 and 7 of radiotherapy. For week 0, nocturia was 3.0 andincreased to 4.7 during weeks 6 and 7 of radiotherapy. The symptom indexincreased from 3 to 4 and the problem index remained unchanged at 1between weeks 0 and 8.

[0089] These data show that administration of HA into the bladder ofPatient D prior to radiotherapy during a course of radiotherapytreatments either prevented or reduced the pain, increased urgency,increased voiding frequency and increased nocturia usually associatedwith radiotherapy for the treatment of prostate cancer.

[0090] A fifth patient, Patient E, was withdrawn from the study aftertwo weeks of HA treatment due to a pre-therapy urinary tract bacterialinfection which did not improve with antibiotic treatment.

[0091] In summary, Patients A, B and D treated with HA as in Example 4,prior to radiotherapy treatments, showed either decreases, no increasesor minimal increases in average pain scale, average urgency scale,average voiding frequency, average nocturia, pain index and symptomindex after 33 radiotherapy treatments during a 7 week period. PatientD, showed no increase in average pain scale, a decrease in averageurgency scale, minimal increases in average voiding frequency, averagenocturia and problem index and a significant increase in symptom index.

[0092] Therefore, patients administered HA into the bladder prior toradiotherapy treatments, during a course of radiotherapy that impingeson the bladder, did not develop the bladder pain, increased urinaryurgency, increased voiding frequency and increased nocturia symptomaticof radiation cystitis.

EXAMPLE 9

[0093] Radiotherapy Followed by HA

[0094] Patients, selected as in Example 1, receive radiotherapy for 7weeks as in Example 3. At week 8, each of these patients showssignificant symptoms of radiation cystitis. At this time, each patientis treated with HA as in Example 4 except that the HA is administered 3times per week (alternate days) for 6 weeks (weeks 8-13) for a total of18 treatments or until the radiation cystitis symptoms resolve.Pre-therapy assessments, as in Example 2, are done during weeks 6 and 7of radiotherapy. Therapy assessments, as in Example 5, are done duringweeks 8-13 or until symptoms resolve. Final symptom index and problemindex are done at week 14 or when radiation cystitis symptoms resolve.

[0095] Each of the patients receiving HA for treatment of radiationcystitis, following a complete course of radiotherapy for prostatecancer, show a decrease in bladder pain, urinary urgency, voidingfrequency and nocturia after from 1 to 6 weeks of HA treatment (weeks8-13), and a decrease in problem index and symptom index by week 14.

[0096] Therefore, administration of HA into the bladder of patientshaving radiation cystitis, following a course of radiotherapy treatmentsfor prostate cancer, decreases the pain, urinary urgency, voidingfrequency and nocturia symptomatic of radiation cystitis.

[0097] It should be understood, of course, that the foregoing relatesonly to a preferred embodiment of the present invention and thatnumerous modifications or alterations may be made therein withoutdeparting from the spirit and the scope of the invention as set forth inthe appended claims.

I claim:
 1. A method, wherein a composition comprising HA, having anaverage molecular weight of not less than 2×10⁵ Daltons, and apharmaceutically acceptable carrier is administered into the bladder ofan animal in an amount effective to prevent radiation cystitis caused byradiotherapy of the bladder area.
 2. The method of claim 1, wherein themolecular weight range of the HA is between about 2×10⁵ and about3.1×10⁶ Daltons.
 3. The method of claim 1 or 2, wherein the amount ofthe HA is between about 5 mg and about 1000 mg.
 4. The method of any oneof claims 1 to 3, wherein the HA is administered in between about 10 mland about 500 ml of the pharmaceutically acceptable carrier.
 5. Themethod of any one of claims 1 to 4, wherein the HA and thepharmaceutically acceptable carrier are administered prior to aradiotherapy treatment.
 6. The method of claim 5, wherein the HA and thepharmaceutically acceptable carrier are administered about 1 minute toabout 4 hours prior to the radiotherapy treatment.
 7. The method ofclaim 5 or 6, wherein the HA and the pharmaceutically acceptable carrierremain in the bladder for about 1 minute to about 4 hours prior to theradiotherapy treatment.
 8. The method of any one of claims 1 to 7,wherein the radiotherapy is for the treatment of a cancer selected fromthe group consisting of bladder cancer, prostate cancer, rectal cancer,uterine cancer and cervical cancer.
 9. The method of claim 8, whereinthe radiotherapy is for the treatment of prostate cancer.
 10. A method,wherein a composition comprising HA, having an average molecular weightof not less than 2×10⁵ Daltons, and a pharmaceutically acceptablecarrier is administered into the bladder of an animal in an amounteffective to reduce radiation cystitis caused by radiotherapy of thebladder area.
 11. The method of claim 10, wherein the average molecularweight of the HA is between about 2×10⁵ and about 3.1×10⁶ Daltons. 12.The method of claim 10 or 11, wherein the amount of HA is between about5 mg and about 1000 mg.
 13. The method of any one of claims 10 to 12,wherein the HA is administered in between about 10 ml and about 500 mlof the pharmaceutically acceptable carrier.
 14. The method of any one ofclaims 10 to 13, wherein the HA and the pharmaceutically acceptablecarrier are administered prior to a radiotherapy treatment.
 15. Themethod of claim 14, wherein the HA and the pharmaceutically acceptablecarrier are administered about 1 minute to about 4 hours prior to theradiotherapy treatment.
 16. The method of claim 14 or 15, wherein the HAand the pharmaceutically acceptable carrier remain in the bladder forabout 1 minute to about 4 hours prior to the radiotherapy treatment. 17.The method of any one of claims 10 to 16, wherein the radiotherapy isfor the treatment of a cancer selected from the group consisting ofbladder cancer, prostate cancer, rectal cancer, uterine cancer andcervical cancer.
 18. The method of claim 17, wherein the radiotherapy isfor the treatment of prostate cancer.
 19. A method, wherein acomposition comprising HA, having an average molecular weight of notless than 2×10⁵ Daltons, and a pharmaceutically acceptable carrier isadministered into the bladder of an animal in an amount effective totreat radiation cystitis subsequent to a course of radiotherapytreatments of the bladder area.
 20. The method of claim 19, wherein themolecular weight range of the HA is between about 2×10⁵ and about3.1×10⁶ Daltons.
 21. The method of claim 19 or 20, wherein the amount ofthe HA is between about 5 mg and about 1000 mg.
 22. The method of anyone of claims 19 to 21, wherein the HA is administered in between about10 ml and about 500 ml of the pharmaceutically acceptable carrier. 23.The method of any one of claims 19 to 22, wherein the HA and thepharmaceutically acceptable carrier remain in the bladder for about 1minute to about 4 hours.
 24. The method of any one of claims 19 to 23,wherein the radiotherapy is for the treatment of a cancer selected fromthe group consisting of bladder cancer, prostate cancer, rectal cancer,uterine cancer and cervical cancer.
 25. The method of claim 24, whereinthe radiotherapy is for the treatment of prostate cancer.